The local treatment of bowel diseases, such as Crohn's disease and ulcerative colitis, or the targeting of drugs to the intestine and in particular to the colon for systemic administration is highly challenging because conventional dosage forms rapidly release the drug in the upper gastrointestinal tract. Upon absorption into the blood stream, the drug is distributed throughout the human body, resulting in potentially severe side effects. In addition, the drug concentration at the site of action, such as the inflamed colon, is low, leading to low therapeutic efficacies. To overcome these restrictions, drug release from the dosage form should ideally be suppressed in the stomach and small intestine, but set on as soon as the target site is reached.
Different approaches have been described in the prior art to allow for site-specific drugs delivery to the small and/or large intestine upon oral administration. Generally, a drug reservoir is surrounded by a film coating, which is poorly permeable to the drug in the upper gastrointestinal tract, but becomes permeable as soon as the target site is reached. Furthermore, drug release might start right after oral administration at a rate which is sufficiently small in order to assure that drug is still present in the dosage form once the target site is reached.
Release of drugs in the colon typically requires a different approach than the release in the small intestine. The colon is susceptible to a number of disease states, including inflammatory diseases, irritable bowel syndrome, constipation, diarrhea, infection and carcinoma. In such conditions, drug targeting to the colon would maximize the therapeutic effectiveness of the treatment. The colon can also be utilized as a portal for the entry of drugs into the systemic circulation and therefore can be effective in the treatment of diseases outside the colon.
Various formulations have been developed for intestinal and in particular colonic drug delivery, including pro-drugs as well as formulated dosage forms, with the latter being more popular since the concept once proofed can be applied to other active agents. Examples for devices and dosage forms for controlled release of an active agent to the colon can be found in U.S. Pat. No. 4,627,851, WO 83/00435 and WO 2007/122374.
Another problem is that colonic diseases are often associated with an insufficient water-resorption and thus a significantly reduced residence time of the drug at the site of action. In order to prevent immediate wash-out a fast release of the drug from the formulation immediately after entering the colon is required. On the other hand, a fast release of the drug is associated with the risk of dose dumping in the upper gastrointestinal tract, for example if the delayed release coating is damaged or for some other reason not sufficient for preventing premature drug release.
Furthermore, the site-specific release of an active agent to the intestine and in particular the colon is extremely sensitive to inter-individual variability. The release is dependent on the individual environment in the gastrointestinal tract, like pH or bacterial flora. This is even true for different stages of inflammation of the mucosa in the small intestine due to individual pH shifts compared to non-inflamed mucosa. This problem occurs for example in ulcerative colitis at different stages of inflammation or in Crohn's disease with different sections of the small intestine affected. This makes it difficult to tailor drug delivery in a way that the drug release takes place not earlier than for example in the terminal ileum.
Even though a variety of technical means to accomplish controlled release and especially site-specific release to the colon is known, there is an incessant need for further pharmaceutical formulations which tailor the delivery of drugs and adapt it to new requirements. Especially for the treatment of inflammations of the mucosa of the small intestine and in particular the colon further pharmaceutical formulations are required which reliably prevent an early release of the drug but at the same time provide release of the drug during its stay at the site of action. Additionally, any excipients in such formulations should be low or not irritating in order to keep the mucosa protected from further irritation.